title: Synthesis and structure-activity relationship studies of O-biphenyl-3-yl carbamates as peripherally restricted fatty acid amide hydrolase inhibitors.
abstract: The peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor URB937 (3, cyclohexylcarbamic acid 3'-carbamoyl-6-hydroxybiphenyl-3-yl ester) is extruded from the brain and spinal cord by the Abcg2 efflux transporter. Despite its inability to enter the central nervous system (CNS), 3 exerts profound antinociceptive effects in mice and rats, which result from the inhibition of FAAH in peripheral tissues and the consequent enhancement of anandamide signaling at CB1 cannabinoid receptors localized on sensory nerve endings. In the present study, we examined the structure-activity relationships (SAR) for the biphenyl region of compound 3, focusing on the carbamoyl and hydroxyl groups in the distal and proximal phenyl rings. Our SAR studies generated a new series of peripherally restricted FAAH inhibitors and identified compound 35 (cyclohexylcarbamic acid 3'-carbamoyl-5-hydroxybiphenyl-3-yl ester) as the most potent brain-impermeant FAAH inhibitor disclosed to date.
authors.affiliation: Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia , via Morego 30, I-16163 Genova, Italy.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Moreno-Sanz
authors.forename: Andrea
authors.initials: A
authors.lastname: Duranti
authors.forename: Laurin
authors.initials: L
authors.lastname: Melzig
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiorelli
authors.forename: Gian Filippo
authors.initials: GF
authors.lastname: Ruda
authors.forename: Giampiero
authors.initials: G
authors.lastname: Colombano
authors.forename: Paola
authors.initials: P
authors.lastname: Mestichelli
authors.forename: Silvano
authors.initials: S
authors.lastname: Sanchini
authors.forename: Andrea
authors.initials: A
authors.lastname: Tontini
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bandiera
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D002219:Carbamates; D004791:Enzyme Inhibitors; D000099252:Fatty Acid Amide Hydrolases